[Physiopathological analysis of stress reaction and drug design].
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Animals↗
Biomedical subjects
H Takeda
Publications and source records attributed to H Takeda.
Calcitonin gene-related peptide (CGRP) and the regulation of cerebral parenchymal vessels.
The role of calcitonin gene-related peptide (CGRP) in the cerebral microcirculation was examined in fourteen anesthetized cats. The local cerebral blood volume (CBV) and blood flow (CBF) in the temporoparietal cortex were measured by our photoelectric method. CBV represents the cumulative dimensions of the parenchymal vascular network. Intracarotid injection of 0.1, 1, and 10 micrograms/kg CGRP8-37, a CGRP antagonist, had no significant effects on CBV and mean arterial blood pressure (MABP). Intracarotid injection of 0.1 and 1 microgram/kg CGRP, but not 0.01 microgram/kg CGRP, increased CBV in a dose-dependent manner (P < 0.05). CBV was initially reduced following 1 microgram/kg CGRP injection, possibly reflecting the marked fall in MABP (P < 0.01) with this dose. Following injection of 0.1 and 1 microgram/kg CGRP, CBF was also increased by +7.3 +/- 7.7 (+10.7%) and +13.1 +/- 4.8 ml/100 g brain/min (+20.4%, P < 0.05) at 15 min. The CBV increase elicited by 1 micrograms/kg CGRP was inhibited (P < 0.05) by preinjection of 10 micrograms/kg CGRP8-37. It is concluded that CGRP has no significant role in the maintenance of resting tone of intracerebral microvessels. However, circulating CGRP dilates the small parenchymal vessels through a specific CGRP receptor, and thereby is involved in the evolution of pathologic conditions.
Animals↗
Bidirectional effects of aminophylline on myocardial ischemia.
BACKGROUND: Aminophylline blocks adenosine receptors and increases levels of plasma catecholamines. We investigated the effect of aminophylline on myocardial ischemia by varying its severity and attempted to identify the mechanism by which aminophylline modulates myocardial ischemia in the canine model. METHODS AND RESULTS: In 41 open-chest dogs, the left anterior descending coronary artery was cannulated and perfused with blood through a bypass tube from the left carotid artery. When coronary blood flow (CBF) was reduced to 80% of the control, aminophylline increased fractional shortening (FS) from 11.0 +/- 0.4% to 18.5 +/- 1.7% (P < .05) and lactate extraction ratio (LER) from 7.5 +/- 0.1% to 13.6 +/- 1.0% (P < .01). The endocardial to epicardial flow ratio (Endo/Epi ratio) of regional myocardium was also increased. Release of adenosine was increased compared with the nonischemic condition (7 +/- 3 versus 28 +/- 5 pmol/mL). Prazosin, an alpha 1-adrenoceptor antagonist, blunted the aminophylline-induced improvement in contractile and metabolic function. Administration of 8-phenyltheophylline, a selective antagonist of adenosine receptors, did not increase FS, LER, or the Endo/Epi ratio when CBF was reduced to 80% of control. When CBF was reduced to 60% of control, aminophylline did not change the metabolic and contractile function. In contrast, when CBF was reduced to 33% of control, release of adenosine was increased markedly (243 +/- 19 pmol/mL) and aminophylline induced decreases in FS, LER, and Endo/Epi ratio similar to those observed with 8-phenyltheophylline. CONCLUSIONS: Aminophylline had opposite effects on the ischemic myocardium depending on the severity of ischemia. It improved mild ischemia but worsened severe ischemia. The beneficial effect of aminophylline was attributable to alpha 1-adrenoceptor stimulation, which improves endomyocardial flow in the ischemic myocardium. The deleterious effect was attributable to the aminophylline-induced blockade of adenosine receptors.
Adenosine↗
Non-amoeboid locomotion of cultured microglia obtained from newborn rat brain.
The movements of cultured microglia obtained from newborn rat brain were examined by video enhanced-differential interference contrast (VEC-DIC) microscopy. Active microglia measured 9.03 +/- 1.06 microns in diameter (mean +/- SD, n = 33; range, 7.03-10.36 microns). The microglia appeared to become smaller with spread of lamellipodia. The short axis of actively moving microglia measured 7.03 +/- 0.49 microns (n = 7). The lamellipodia were thin, transparent and developed rapidly around the cell body (maximal speed of extension, 4 or 5 microns/s). When shear stress from the medium was applied to the surface of cultured cells, the microglia swam with flat lamellipodia serving as sails in the stream. Spontaneous non-amoeboid movements of microglia were observed: they pivoted, circled and marched in various directions using their lamellipodia. The angular speed of rotation was maximally 3 degrees/s. In 5 marching cells, the average speed (distance/s) was calculated at 1.01 +/- 0.54 microns/s (ca. 60 microns/min or 3.6 microns/h).
Animals↗
Glycine-extended progastrin processing intermediates induce H+,K(+)-ATPase alpha-subunit gene expression through a novel receptor.
Biologically active amidated gastrin is synthesized by carboxyl-terminal alpha-amidation of a glycine-extended progastrin post-translational processing intermediate (G-Gly). Although plasma levels of G-Gly are equivalent to those of gastrin, G-Gly has essentially no acute effect on gastric acid secretion. However, we have observed that inhibition of gastrin amidation leads to increased plasma concentrations of G-Gly and enhanced gastric acid secretion. We hypothesized, therefore, that G-Gly might have a chronic effect to increase H+,K(+)-ATPase expression in gastric parietal cells. In the present studies, we observed that a 2-day preincubation with G-Gly significantly enhanced histamine-stimulated [14C]aminopyrine uptake by isolated canine gastric parietal cells but acutely administered G-Gly had no effect. On Northern blot analysis, both G-Gly and gastrin dose-dependently increased H+,K(+)-ATPase alpha-subunit gene expression with maximal induction (225 +/- 35 and 170 +/- 29% of basal, mean +/- S.E.) achieved at concentrations of 10(-9) M G-Gly and 10(-8) M gastrin, respectively. Using an H+,K(+)-ATPase alpha-subunit gene-luciferase chimeric reporter construct transfected into primary cultured parietal cells, we observed that both G-Gly and gastrin increased luciferase activity in a manner similar to that obtained by Northern blot analysis. L365,260, a specific gastrin/CCKB receptor antagonist, completely reversed the stimulation of luciferase activity induced by gastrin but had no effect on G-Gly-stimulated activity. Gastrin increased [Ca2+]i, although G-Gly did not, however, genistein (a tyrosine kinase inhibitor) significantly reduced induction of luciferase activity by both G-Gly and gastrin. Specific binding of 125I-Leu15-G2-17-Gly to gastric parietal cells was dose-dependently displaced by G2-17-Gly but not by gastrin nor L365,260. Gastrin peptides truncated at the carboxyl- (G1-13) and amino terminus (G5-17-Gly) both induced H+,K(+)-ATPase alpha-subunit gene expression and inhibited 125I-Leu15-G2-17-Gly binding, but were less potent than G2-17-Gly. These data indicate that G-Gly may have a functional role in potentiating gastric acid secretagogue action via enhanced expression of the gene responsible for H+ generation through action at a novel receptor that can be distinguished from the gastrin/CCKB receptor. Thus, both the substrate and product of the terminal progastrin processing reaction appear to have complementary functions in regulation of gastric acid secretion.
Aminopyrine↗
Beta-migrating very low density lipoproteins induce foam cell formation in mouse mesangial cells.
To elucidate whether beta-migrating very low density lipoproteins (beta-VLDL) induce foam cell formation in mesangial cells or not, surface binding and foam cell formation with beta-VLDL were studied in mouse mesangial cells. Specific binding kinetics for beta-VLDL and low density lipoproteins (LDL) on the mesangial cells were observed with Kd = 3.8 and 13.7 micrograms/ml, and Bmax = 65.9 and 71.9 ng/ml cell protein at 4 degrees C, respectively. The binding of beta-VLDL was inhibited by excess amounts of LDL or beta-VLDL, but not by acetyl-low density lipoproteins. Ligand blotting using beta-VLDL or LDL and immunoblotting using anti-human LDL receptor monoclonal antibody detected the same apparent single protein (approx. 130 kDa). Incorporation of [14C]oleate into cholesteryl ester in mouse mesangial cells was enhanced by beta-VLDL to 3-fold higher than that by LDL, and it was inhibited by chloroquine or anti-human LDL receptor monoclonal antibody. The light microscopic findings also demonstrated that cholesteryl ester deposition increased in these cells incubated with beta-VLDL, but not with LDL. In conclusion, beta-VLDL was specifically taken up by receptor-mediated endocytosis in mouse mesangial cells through LDL receptors, resulting in foam cell formation.
Animals↗
Pharmacological effects of concomitant administration of beta-adrenoceptor blocker and agonist in normal subjects: characterization by heart rate response to exercise. Effects of beta-blocker combined with beta-agonist.
The effects of a combination regimen of metoprolol and beta 1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion. During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats.min-1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats.min-1, respectively. Peak oxygen uptake was also significantly decreased by both regimens. We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective beta-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for beta-adrenoceptor blocker therapy in patients with chronic heart failure.
Adrenergic beta-Agonists↗
Preventive effect of simultaneously infused lipid emulsion against thrombophlebitis during postoperative peripheral parenteral nutrition.
A prospective, randomized study was conducted to determine whether simultaneous infusion of lipid emulsion with an amino acid-dextrose-electrolyte solution would reduce the incidence of thrombophlebitis (TP) during postoperative peripheral parenteral nutrition (PPN). Thirty patients who had undergone gastric resection for adenocarcinoma were randomly divided into two groups according to whether they were infused with 10% lipid emulsion (group A) or 5% glucose solution (group B) simultaneously with the amino acid-glucose solutions. The total osmolarity of the infusion solutions in each group was 853 mOsm/l. The incidence of complications due to TP, namely, redness and/or edema beneath the cannula insertion site and/or pain, was investigated. There were no differences in the background characteristics of the patients in groups A and B, except regarding concurrent resection of other organs (P = 0.03). The incidence of edema in group A was significantly lower than in group B on postoperative days 2 and 4, although there was no difference in the incidence of redness and pain between the two groups. These findings suggest that the simultaneous infusion of lipid emulsion has a preventive effect against TP during postoperative PPN, and may be a practical means of providing PPN after gastrointestinal surgery.
Adenocarcinoma↗
Pentoxifylline ameliorates postischemic delayed hypoperfusion of the cerebral cortex following cardiac arrest in cats.
Two major events occurring in the cerebral hemodynamics after successful resuscitation from cardiac arrest are reactive hyperemia and postischemic hypoperfusion. We examined the effect of pentoxifylline on the feline cerebral hemodynamics following cardiac arrest. Fifteen cats were anesthetized and artificially ventilated. Using our photoelectric method, the local cerebral blood volume (CBV), mean transit time of blood (MTT), and cerebral blood flow (CBF) in the parietotemporal region were measured. Thoracotomy was performed, and cardiac arrest (ventricular fibrillation) was induced by direct application of a 2-V DC countershock. The heart was resuscitated with a DC countershock at 30 sec after cardiac arrest. In 9 cats, pentoxifylline (25 mg/kg) was infused into the femoral vein at 5 min before cardiac arrest (PTX group). The other 6 cats served as controls (control group). In both groups, the CBV, CBF and mean arterial blood pressure (MABP) overshot the control levels just after resuscitation, whereas the MTT was decreased. In the control group, postischemic hypoperfusion was detected at 30-180 min after resuscitation from cardiac arrest (CBF (ml/100 g/min): 51 +/- 4 (control), 38 +/- 4 (30 min, p < 0.05), and 23 +/- 3 (180 min, p < 0.05)). However, the postischemic hypoperfusion was not observed in the PTX group. Pentoxifylline ameliorated postischemic delayed hypoperfusion in the cerebral cortex after a short period of cardiac arrest. Pentoxifylline may be useful in the emergency situations following cardiac arrest.
Animals↗
The effect of a thromboxane A2 receptor antagonist BAY-u-3405 on experimental allergic reactions.
The effect of a novel thromboxane A2 receptor antagonist, BAY-u-3405, on experimental allergic airway and skin reactions was studied in vivo. At doses of 3-30 mg/kg BAY-u-3405 clearly inhibited the U-46619-induced increase in respiratory resistance (Rrs) in guinea pigs. BAY-u-3405 at doses of 3 and 30 mg/kg inhibited the aerosolized antigen-induced biphasic increase in respiratory resistance in guinea pigs. Moreover, BAY-u-3405 inhibited repeated aeroantigen-induced airway hyperactivity and airway inflammation in mice. In IgE antibody-mediated biphasic skin reactions in mice, both immediate and late-phase reactions were inhibited by 10 mg/kg of BAY-u-3405. These results demonstrate the efficacy of BAY-u-3405 on the antigen-induced late-phase reactions in the airway and skin in guinea pigs and mice, and antigen-induced airway hyperactivity in mice.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
The effect of a TXA2 receptor antagonist ON-579 on experimental allergic reactions.
The effect of a thromboxane A2 (TXA2) receptor antagonist, ON-579, on experimental allergic skin and airway reactions was studied in vivo. ON-579 at doses of 1 and 20 mg/kg clearly inhibited U-46619-induced increases in respiratory resistance (Rrs) in guinea pigs. ON-579 at doses of 1, 20 and 50 mg/kg inhibited the aerosolized antigen-induced biphasic increase in Rrs in guinea pigs. Moreover, ON-579 clearly inhibited repeated aeroantigen-induced airway hyperreactivity in guinea pigs. ON-579, however, did not have any significant effects on allergic cutaneous reactions in rats. These results suggest that ON-579 is a relatively selective TXA2 antagonist, especially in the airways, and indicate the efficacy of ON-579 on antigen-induced increase in airway resistance and antigen-induced airway hyperreactivity in guinea pigs.
Aerosols↗
Effects of ventricular arrhythmia on the cerebral microcirculation in cats.
To test the widely believed but poorly proved hypothesis that the cerebral symptoms observed during ventricular arrhythmia are caused by a reduced cerebral blood supply, we examined the effects of single and multiple ectopic ventricular beats (or ventricular tachycardia of short duration) on the cerebral microcirculation. Six anesthetized cats were used. Ectopic ventricular systoles of various sequences were produced by electrically stimulating the ventricle through a bipolar needle-type electrode for 1 to 50 times at a rate of 300/min. The local cerebral blood volume (CBV) and blood flow (CBFLD) in the cortex were measured continuously employing the photoelectric and laser Doppler methods. CBV reflects the cumulative dimensions of the cerebrocortical microvessels. Ectopic ventricular contractions, as confirmed by electrocardiograms, always reduced the CBV and arterial blood pressure in a total of 104 attempts. The CBV reductions ranged from 0.20 +/- 0.03 vol% for a single ectopic beat to approximately 0.6-0.8 vol% for runs of 8 or more beats. The CBFLD reductions measured with the laser Doppler flowmeter were 10-35%. The reductions in CBV and CBFLD during the ventricular arrhythmia could be attributed to the abrupt and marked reductions in arterial blood pressure. Runs of ectopic ventricular beats have significant effects on the cerebral microcirculation, whether clinically apparent or not.
Animals↗
V-src kinase shifts the cadherin-based cell adhesion from the strong to the weak state and beta catenin is not required for the shift.
The elevation of tyrosine phosphorylation level is thought to induce the dysfunction of cadherin through the tyrosine phosphorylation of beta catenin. We evaluated this assumption using two cell lines. First, using temperature-sensitive v-src-transfected MDCK cells, we analyzed the modulation of cadherin-based cell adhesion by tyrosine phosphorylation. Cell aggregation and dissociation assays at nonpermissive and permissive temperatures indicated that elevation of the tyrosine phosphorylation does not totally affect the cell adhesion ability of cadherin but shifts it from a strong to a weak state. The tyrosine phosphorylation levels of beta catenin, ZO-1, ERM (ezrin/radixin/moesin), but not alpha catenin, vinculin, and alpha-actinin, were elevated in the weak state. To evaluate the involvement of the tyrosine phosphorylation of beta catenin in this shift of cadherin-based cell adhesion, we introduced v-src kinase into L fibroblasts expressing the cadherin-alpha catenin fusion protein, in which beta catenin is not involved in cell adhesion. The introduction of v-src kinase in these cells shifted their adhesion from a strong to a weak state. These findings indicated that the tyrosine phosphorylation of beta catenin is not required for the strong-to-weak state shift of cadherin-based cell adhesion, but that the tyrosine phosphorylation of other junctional proteins, ERM, ZO-1 or unidentified proteins is involved.
Animals↗
Tc-99m DTPA-HSA SPECT in a case of hemangioma of the spleen.
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Female↗
Evaluation of the effect of lansoprazole in suppressing acid secretion using 24-hour intragastric pH monitoring.
The acid-inhibitory effect of lansoprazole was evaluated in comparison with that of famotidine and omeprazole by using 24-h intragastric pH monitoring in 10 young, healthy Japanese volunteers. Lansoprazole 20 mg once daily in the morning was superior to famotidine 20 mg twice daily, omeprazole 20 mg once daily in the morning in reducing 24-h intragastric acidity. Unlike famotidine, whose acid-inhibitory effect was observed mainly at night, both lansoprazole and omeprazole inhibited both daytime and nocturnal acid secretion, with the maximal effect occurring in the afternoon. Although the daily profile of acid-inhibitory action of lansoprazole was similar to that of omeprazole, the acid-inhibitory effect of lansoprazole was more potent than that of omeprazole at any time of the day. These results indicate that lansoprazole at a dosage of 30 mg once daily in the morning produced the most potent inhibition of acid secretion in young Japanese volunteers, compared with famotidine 20 mg twice daily and omeprazole 20 mg once in the morning.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Clinical efficacy of lansoprazole in eradication of Helicobacter pylori.
A randomized, single-blind study was designed to assess the effect of lansoprazole alone and lansoprazole plus amoxicillin on the healing and eradication rates in Helicobacter pylori-associated peptic ulcer disease. Seventy-nine patients with gastric ulcers and 54 patients with duodenal ulcers were randomly assigned to two treatment groups. Group 1 received lansoprazole 30 mg daily for 8 weeks for gastric ulcers or 6 weeks for duodenal ulcers. Group 2 received the group 1 regimen plus amoxicillin 2 g daily for 2 weeks. Healing rates at 8 weeks for the gastric ulcer patients were 92 and 84% in groups 1 and 2, respectively (p = not significant). Healing rates at 6 weeks for duodenal ulcers were 96% in group 1 and 100% in group 2 (p = not significant). The eradication rates of H. pylori for gastric ulcer patients were 21 and 54% in groups 1 and 2, respectively (p < 0.05). The H. pylori eradication rates for duodenal ulcer patients were 5 and 73% in groups 1 and 2, respectively (p < 0.001). The H. pylori eradication rates in group 2 were significantly higher than in group 1. Lansoprazole was effective for eradicating H. pylori in this study.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Activated leukocytes, endothelial cells, and effects of pentoxifylline: observations by VEC-DIC microscopy.
Using video-enhanced contrast (VEC)-differential interference contrast (DIC) microscopy, ultrastructural observations were made of the activation of polymorphonuclear leukocytes (PMNLs), the interaction between activated PMNLs and endothelial cells (ECs), and the effects of pentoxifylline (PTX). The ECs were obtained from a commercial source as human umbilical cord vein endothelial cells (HUVECs) or were obtained from pig or rat brains. They were cultured on a coverglass with DMEM for about 1 week. The human PMNLs were obtained from the authors' venous blood. The control appearance of the PMNLs resembled an elastic ball covered with fine villi. The PMNL was activated spontaneously and became flattened on the glass surface within 10 min in the observation chamber. The activation of the PMNLs was estimated arbitrarily from the polymorphous changes in cell shape, agitation of the intracellular granules, and apparent increase in adhesiveness. Preadministered PTX prevented such PMNL activation, and the PMNLs remained round for more than 15 min. PMNL activation was accelerated by chemoattractants (PAF, fMLP, and PMA). In one case, a PMNL that had been activated by PMA tended to recover its round shape with PTX, but finally ended by swelling and bursting. When PMNLs were introduced into the EC-containing chamber, they became entrapped by the ECs and activated, with degranulation followed by release of a smoke-like material. After about 3 h, the EC with an attached PMNL shrank and fell into a state of coagulation necrosis. When PTX was introduced at the time of adhesion of the flattened PMNL, the PMNL appeared to be deactivated, becoming smaller and assuming its previous round shape, and detached from the EC. PTX prevented the spontaneous activation of PMNLs, and of deactivated PMNLs even after their adherence to the endothelium.
Animals↗
A less invasive Emax estimation method for weaning from cardiac assistance.
The maximum elastance of the ventricle (Emax) is a strong candidate for a quantitative index used for determination of the timing of weaning the patient from a left ventricular assist device (LVAD). This paper presents a new and less invasive method for deriving Emax of the left ventricle under the LVAD assistance. In this method (the CoP method), Emax can be calculated from two different end-systolic points which are produced by changing the drive phase of LVAD without any vascular clamping and any direct measurement of the left ventricular volume. Animal experiments indicated that the CoP method is useful when the measured left ventricular flow and pressure are employed. Moreover, a new technique for estimating the left ventricular flow was developed to make the CoP method less invasive without direct measurement of the flow. The technique could considerably improve the estimation accuracy of the flow in the co-pulsation mode in comparison with the previous one proposed by the authors. However, it has been revealed that the estimation accuracy of the left ventricular flow was not globally high enough to apply the CoP method to clinical cases in spite of its much less invasiveness.
Animals↗